Biodegradable polymers are gaining attention as drug delivery systems. R. Langer, New Methods of Drug delivery, 249 Science 1527-1533 (1990); B. Jeong et al., Biodegradable Block Copolymers as Injectable Drug-delivery Systems, 388 Nature 860-862 (1997). Delivering bioactive agents from a biodegradable delivery system is highly desirable because the need for a surgical procedure to remove the delivery system is avoided. Controlled release of bioactive agents can reduce the required frequency of administration by maintaining the concentration of the therapeutic agent at desired levels. One important means of maintaining the proper concentration is by controlling the degradation rate of the biodegradable drug delivery system.
The biodegradable hydrophobic polymers widely used as drug carriers include polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of lactic acid and glycolic acid (PLGA), polycaprolactone (PCL), polyorthoester (POE), polyamino acid (PAA), polyanhydride (PAH), polyphosphazine, polyhydroxybutyric acid (PHB), polydioxanone (PDO), etc. Such polymers have good biocompatibility and the desirable feature of being hydrolyzed and decomposed in a living body to side products which have no toxicity. For these reasons they are widely used as drug carriers. In particular, since these polymers are insoluble in water formulations some drugs are incorporated into the polymer matrix and then implanted in the body in the form of microspheres, nanospheres, films, sheets or rods, whereby the drug is slowly released and exerts a sustained therapeutic effect. In these types of formulations, the polymers themselves are finally decomposed in the body. However, these polymers have a low affinity for water-soluble drugs and it is very difficult to incorporate a large amount of drug into the polymer matrix. Even if the drug is effectively incorporated into the polymer matrix, the problem of initial burst release (which means a phenomenon whereby a large amount of drug is released within the first few hours) may occur when it is implanted into the body.
The A-B, B-A-B, or A-B-A type block copolymers, wherein A is a hydrophilic polymer block and B is a hydrophobic biodegradable polymer block, have been used as drug carriers for the delivery of physiologically active materials in the form of polymeric micelles, nanospheres, microspheres, gels, etc. These block copolymers have desirable properties such as good biocompatibility and the ability to form core-shell type polymeric micelles in an aqueous solution where the core is composed of the hydrophobic blocks and the shell is composed of the hydrophilic blocks. The micellar formulation wherein a poorly water soluble drug can be incorporated into the inside of polymeric micelle to give a micellar solution are good drug carriers for hydrophobic drugs. However, since the drug is incorporated via hydrophobic interaction between the hydrophobic drug and the hydrophobic polymer, the incorporation efficiency of highly hydrophobic drugs is excellent, but water-soluble hydrophilic drugs can hardly be incorporated at all into those polymeric micelles.
Kataoka et al.(EP 721,776 A1) have developed a method for incorporating a charged water-soluble drug into the inside of a polymeric micelle using a block copolymer consisting of a non-charged block and a charged block. The charged block used by Kataoka is a polyamino acid having an ionic side chain, such as polyaspartic acid, polyglutamic acid, polylysine, polyarginine, or polyhistidine. However, they are not biodegradable in a living body. In addition since the charged block may include several functional groups having electric charges, when they are combined inside the molecule via electrostatic binding with a drug having multiple ionic groups, such as peptides or proteins, they may decrease the stability of such drugs.
In view of the foregoing, development of a drug carrier for cationic drug delivery that is biocompatible and biodegradable will be appreciated and desired. Thus, the present invention provides a new type of negatively charged amphiphilic block copolymer that is biocompatible and biodegradable and which can effectively deliver the drug without a decrease in its stability. By forming a complex with a cationic drug via electrostatic interaction, the anionic amphiphilic block copolymer of the present invention can effectively incorporate a water-soluble positively charged drug into the amphiphilic block copolymer. In addition, the block copolymer of the present invention is readily susceptible to metabolic degradation after incorporation and delivery of the drug into the cell.